The extensive variation at some of the immune response genes is central amongst the host genetic determinants that contribute to the variability in risk of virtually all human diseases. We have studied the genetic effects of the highly polymorphic KIR and HLA loci, as well as other related, less polymorphic loci on several diseases. Our contributions to the general understanding of these effects are summarized here. Variation at the HLA class I locus has a stronger influence on HIV-1 disease outcome than that of any other genetic locus identified to date. HLA class I molecules have two fundamental roles in determining the strength of the immune response against HIV: 1) regulation of the acquired response through presentation of antigenic epitopes to cytotoxic T lymphocytes (CTL), and 2) modulation of the innate response by serving as ligands for the killer cell immunoglobulin-like receptors (KIR) expressed on natural killer (NK) cells. In both regards, HLA-B has been the primary focus relative to HLA-A and C because the strongest genetic and functional associations with HIV disease outcomes have involved this locus. Recently, however, a scan for genetic variants that influence control of viral load indicated that a dimorphism 35kb upstream of the HLA-C gene (-35C/T) had one of the two strongest genome-wide effects on the level of HIV plasma viremia in early, established HIV infection. Notably, the -35C variant that associates with low viral load has also been shown to associate with high HLA-C mRNA levels in a co-dominant manner amongst a group of individuals of European ancestry. These findings suggest that certain HLA-C allotypes may have a primary role in restricting HIV replication through innate and/or acquired immune mechanisms that have been previously overlooked. Using a cohort of 1698 individuals, we showed that the -35 variant associates very strongly with HIV outcomes during the early phase of infection by influencing steady- state viral load, and to a weaker extent with the very late phase of infection by influencing time to death. These temporal data implicate two at least partially distinct mechanisms of HIV restriction associated with the -35 variant. No individual HLA-C allotype appears to be clearly better than others in terms of controlling HIV through antigen presentation to CTL, unlike that which has been observed at the HLA-B locus. However, higher levels of HLA-C on target cell surfaces may generally result in more effective antigen presentation to CTL or enhance NK cell activity, thus boosting the immune system and leading to better viral control by the host. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells. It is well established that HLA class I plays an important role in determining the rate of progression to AIDS after infection with HIV-1. It is less clear, however, how HLA diversity affects HIV transmission. We previously showed that the HLA-Bw4 and Bw6 epitopes of the HLA-B molecules are associated with risk for HIV transmission between heterosexual couples. The presence of HLA-Bw4 in HIV-1-infected men was associated with a decreased risk of male-to-female HIV-1 transmission. More recently, we further investigated the association of individual HLA-B alleles for their respective contributions to the risk of HIV-1 transmission from HIV-infected men to their female partners. We also tested for an association of HLA-B alleles present in the female partners of HIV+ carriers on risk of becoming infected. Among the HIV-infected men, three HLA-B alleles showed a significant association with infectivity. Men positive for HLA-B*35Px (B*3502, B*3503, and B*5301), a group of alleles previously associated with rapid AIDS progression, showed an increased risk of transmitting the virus to their female partners, whereas men positive for B*27 or B*57, alleles which is associated with slow AIDS progression, transmitted the virus to their partners less frequently. On the other hand, HLA polymorphisms among female sex partners did not affect their susceptibility to HIV infection. In summary, class I HLA polymorphism appears to affect HIV-1 infectivity but not susceptibility. The HLA alleles B*35Px, B*27 and B*57 may influence both HIV-1 transmission and post-infection risk of AIDS through control of HIV-1 RNA levels in semen and blood. NK cells are critical in the early containment of viral infections. Epidemiological and functional studies have shown an important role of NK cells expressing specific killer immunoglobulin-like receptors (KIRs) in the control of HIV-1 infection, but little is known about the mechanisms that determine the expansion of these antiviral NK cell populations during acute HIV-1 infection. One particular activating KIR (KIR3DS1), in combination with its putative ligand, an HLA-B allele with isoleucine at position 80 (HLA-B Bw480I), has been previously shown by us to be associated with slower HIV-1 disease progression. They have also shown that KIR3DS1+ NK cells can effectively suppress HIV-1 replication in HLA-B Bw480I+ target cells in vitro. Furthermore, a subset of inhibitory alleles from the same locus, KIR3DL1, that show high cell surface expression levels have similarly been associated with slower disease progression toward AIDS in the presence of their ligand, HLA-B Bw480I. However, the mechanisms underlying their protective role are not understood. In collaboration with investigators at Harvard University, we assessed clonal NK cell expansions during acute HIV-1 infection by quantitative PCR and flow cytometric analysis. The results indicate that NK cells expressing the activating receptor KIR3DS1 and, to a lesser extent, the inhibitory receptor KIR3DL1 specifically expand in acute HIV-1 infection in the presence of HLA-B Bw480I, the putative HLA class I ligand for KIR3DL1/3DS1. The early accumulation of highly activated NK cells may provide a potent first-line defense allowing for the initial control of acute HIV-1 replication while adaptive immune responses are still developing. These data demonstrate for the first time the impact of the HLA class I ligands on clonal NK cell expansions during an acute human viral infection.